Targeting neurogenesis ameliorates danger assessment in a mouse model of Alzheimer's disease

Shruster, Adi; Offen, Daniel

doi:10.1016/j.bbr.2013.12.028

Cited by 25 publications

(9 citation statements)

References 70 publications

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“…Because the hippocampus contains neural stem cells, the extensive loss of hippocampal volume in the 3xTg/Polβ mice could be explained by increased cell death and/or reduced neurogenesis. A DNA repair compromised animal model has been reported to have reduced levels of adult neurogenesis ( 74 ), a phenotype that has also been observed in AD mouse models ( 75 , 76 ). We asked whether the reduced hippocampal volume measured in the 3xTg/Polβ mice was due to a decline in adult neurogenesis.…”

Section: Resultsmentioning

confidence: 93%

DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes

Sýkora

Misiak

Wang

et al. 2014

Nucleic Acids Research

123

118

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We explore the role of DNA damage processing in the progression of cognitive decline by creating a new mouse model. The new model is a cross of a common Alzheimer's disease (AD) mouse (3xTgAD), with a mouse that is heterozygous for the critical DNA base excision repair enzyme, DNA polymerase β. A reduction of this enzyme causes neurodegeneration and aggravates the AD features of the 3xTgAD mouse, inducing neuronal dysfunction, cell death and impairing memory and synaptic plasticity. Transcriptional profiling revealed remarkable similarities in gene expression alterations in brain tissue of human AD patients and 3xTg/Polβ+/− mice including abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in base excision repair capacity can render the brain more vulnerable to AD-related molecular and cellular alterations.

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Section: Resultsmentioning

confidence: 93%

DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes

Sýkora

Misiak

Wang

et al. 2014

Nucleic Acids Research

123

118

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“…It is well-known that the hypothalamus is a crucial organ in the regulation energy and glucose metabolism. The hippocampus is a brain region where neurogenesis continues throughout life and its neuronal death results in altered neuronal circuits and impaired learning and memory [ 49 ]. Neurogenesis in the brain, especially the hippocampus, ameliorates cognitive dysfunction by insulin and Wnt signaling [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…The hippocampus is a brain region where neurogenesis continues throughout life and its neuronal death results in altered neuronal circuits and impaired learning and memory [ 49 ]. Neurogenesis in the brain, especially the hippocampus, ameliorates cognitive dysfunction by insulin and Wnt signaling [ 48 , 49 ]. Therefore, neuronal loss in the hippocampus due to β-amyloid deposition might induce glucose dysregulation by exacerbating peripheral insulin resistance, especially in the liver.…”

Section: Discussionmentioning

confidence: 99%

Red peppers with moderate and severe pungency prevent the memory deficit and hepatic insulin resistance in diabetic rats with Alzheimer’s disease

et al. 2015

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BackgroundDementia induced by β-amyloid accumulation impairs peripheral glucose homeostasis, but red pepper extract improves glucose homeostasis. We therefore evaluated whether long-term oral consumption of different red pepper extracts improves cognitive dysfunction and glucose homeostasis in type 2 diabetic rats with β-amyloid-induced dementia.MethodsMale diabetic rats received hippocampal CA1 infusions of β-amyloid (25–35) (AD) or β-amyloid (35–25, non-plaque forming), at a rate of 3.6 nmol/day for 14 days (Non-AD). AD rats were divided into four dietary groups receiving either 1% lyophilized 70% ethanol extracts of either low, moderate and severe pungency red peppers (AD-LP, AD-MP, and AD-SP) or 1% dextrin (AD-CON) in Western diets (43% energy as fat).ResultsThe ascending order of control < LSP < MSP and SSP potentiated the phosphorylation of CREB and GSK and inhibited Tau phosphorylation in the hippocampus which in turn inhibited β-amyloid accumulation. The inhibition by MP and SP reduced the memory deficit measured by passive avoidance test and water maze test. Furthermore, the accumulation of β-amyloid induced glucose intolerance, although serum insulin levels were elevated during the late phase of oral glucose tolerance test (OGTT). All of the red pepper extracts prevented the glucose intolerance in AD rats. Consistent with OGTT results, during euglycemic hyperinulinemic clamp glucose infusion rates were lower in AD-CON than Non-AD-CON with no difference in whole body glucose uptake. Hepatic glucose output at the hyperinsulinemic state was increased in AD-CON. β-amyloid accumulation exacerbated hepatic insulin resistance, but all red pepper extract treatments reversed the insulin resistance in AD rats.ConclusionsThe extracts of moderate and severe red peppers were found to prevent the memory deficit and exacerbation of insulin resistance by blocking tau phosphorylation and β-amyloid accumulation in diabetic rats with experimentally induced Alzheimer’s-like dementia. These results suggest that red pepper consumption might be an effective intervention for preventing age-related memory deficit.

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“…In a 3xTgAD mouse model bearing mutations in APP, PS1, and Tau genes, restoration of neurogenesis through chronic overexpression of Wnt3a in the ventral region of the dentate gyrus leads to correction of impairments in danger assessment. The effect is neurogenesis dependent since ablation of neurogenesis via X-irradiation prevents the recovery (Shruster and Offen 2014).…”

Section: Age-related Cognitive and Neurogenesis Decline In Animalsmentioning

confidence: 99%

Role of Adult Hippocampal Neurogenesis in Cognition in Physiology and Disease: Pharmacological Targets and Biomarkers

Costa

Lugert

Jagasia

2015

Handbook of Experimental Pharmacology

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Adult hippocampal neurogenesis is a remarkable form of brain structural plasticity by which new functional neurons are generated from adult neural stem cells/precursors. Although the precise role of this process remains elusive, adult hippocampal neurogenesis is important for learning and memory and it is affected in disease conditions associated with cognitive impairment, depression, and anxiety. Immature neurons in the adult brain exhibit an enhanced structural and synaptic plasticity during their maturation representing a unique population of neurons to mediate specific hippocampal function. Compelling preclinical evidence suggests that hippocampal neurogenesis is modulated by a broad range of physiological stimuli which are relevant in cognitive and emotional states. Moreover, multiple pharmacological interventions targeting cognition modulate adult hippocampal neurogenesis. In addition, recent genetic approaches have shown that promoting neurogenesis can positively modulate cognition associated with both physiology and disease. Thus the discovery of signaling pathways that enhance adult neurogenesis may lead to therapeutic strategies for improving memory loss due to aging or disease. This chapter endeavors to review the literature in the field, with particular focus on (1) the role of hippocampal neurogenesis in cognition in physiology and disease; (2) extrinsic and intrinsic signals that modulate hippocampal neurogenesis with a focus on pharmacological targets; and (3) efforts toward novel strategies pharmacologically targeting neurogenesis and identification of biomarkers of human neurogenesis.

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Targeting neurogenesis ameliorates danger assessment in a mouse model of Alzheimer's disease

Cited by 25 publications

References 70 publications

DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes

DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes

Red peppers with moderate and severe pungency prevent the memory deficit and hepatic insulin resistance in diabetic rats with Alzheimer’s disease

Role of Adult Hippocampal Neurogenesis in Cognition in Physiology and Disease: Pharmacological Targets and Biomarkers

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